This research proposal will focus on the manner in which interaction between drugs and autonomic nerves determines the net response of an organ to pharmacologic agents. The denervated hearts of both dog and rat will be utilized as test systems because they provide a means of studying organ responses in the absence of indirect effects mediated through autonomic nerves. By comparing the qualitative and quantitative responses of the innervated versus the denervated organs to a variety of sympathomimetic, parasympathomimetic, antiarrhythmic, blocking, and other agents it will be possible to characterize the modes of interaction between drugs and autonomic nerves. At the same time, valuable information can be obtained concerning the physiology and pharmacology of the denervated and/or transplanted heart and on the mechanism of denervation supersensitivity. The experiments will utilize a number of different preparations: 1) The acute dog on total cardiopulmonary bypass allows separate and simultaneous assessment of cardiac, resistance and capacitance responses to pharmacologic and physiological interventions; 2) The isolated rat papillary muscle from normal and transplanted rat hearts to permit direct measurement of the responses of cardiac muscle to drugs and to physiologic stimuli (e.g., Ca ions) both in the presence and absence of intrinsic neural elements; 3) The selectively sympathectomized or vagotomized dog heart which will allow us to observe the responses of the heart in the presence of only one component of the reciprocal autonomic innervaton.